This invention relates to drug delivery. More particularly, this invention relates to biodegradable tri-block copolymers that undergo reverse thermal gelation at about 30° C. That is, these polymers undergo a sol-to-gel transition as their temperature is raised from room temperature to body temperature. Thus, polymer solutions can be injected into an individual, and the solutions then undergo a transition to a gel, thereby forming a depot from which a drug can be released over time.
Biodegradable thermoreversible polymers in aqueous solutions that undergo the sol-to-gel phase transition upon temperature changes have been developed for their applications as delivery systems for drugs, cells, proteins, and genes. Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Nature 1997, 388, 860-862; Rathi, R.; Zentner, G. M. U.S. Pat. No. 5,702,717, 1999; Zentner, G. M.; Rathi, R.; Shih, C.; McRea, J. C.; Seo, M.-H.; Oh, H.; Rhee, B. G.; Mestecky, J.; Moldoveanu, Z.; Morgan, M. J. Controlled Release 2001, 72, 203-215; Li, Z.; Ning, W.; Wang, J.; Choi, A.; Lee, P.-Y.; Tyagi, P.; Huang, L. Pharm. Res. 2003, 20, (6), 884-888. Such biodegradable thermoreversible polymers have typically been engineered from hydrophilic poly(ethylene glycol) block(s) and hydrophobic biodegradable block(s). With an exquisite balance of hydrophilicity and hydrophobicity, aqueous solutions of the engineered polymers have undergone the unique phase transition at below body temperature. Zentner et al., supra; Shim, M. S.; Lee, H. T.; Shim, W. S.; Park, I.; Lee, H.; Chang, T.; Kim, S. W.; Lee, D. S. J. Biomed. Mater. Res. 2002, 61, (2), 188-196; Jeong, B.; Bae, Y. H.; Kim, S. W. Macromolecules 1999, 32, 7064-7069. This unique gelation of the polymers has been considered useful for their applications for the formulation of sensitive macromolecular therapeutics, as well as for small molecular drugs, because a mild temperature rise upon injection results in polymeric gel depots in vivo, which can control drug release.
In early work on thermogelling biodegradable polymers, Jeong et al. synthesized di- and tri-block copolymers of PEG and poly(lactide-co-glycolide) (PLGA) to develop polymeric gels, which were suggested to find applications as injectable drug delivery systems. Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Nature 1997, 388, 860-862. Later, the use of low molecular weight PEG led to thermogelling polymers that uniquely undergo gelation upon a temperature rise. Zentner et al., supra; Shim et al., supra; Jeong, B.; Bae, Y. H.; Kim, S. W. Macromolecules 1999, 32, 7064-7069. Thermogelling properties of the tri-block copolymers synthesized from PEG and PLGA were affected by the chemical structure, concentration, and hydrophobic block length of the block copolymers. Thermogelling polymers with longer hydrophobic biodegradable PLGA blocks usually underwent gelation at lower temperatures than the polymers with shorter hydrophobic blocks. Shim et al., supra; Lee, D. S.; Shim, M. S.; Kim, S. W.; Lee, H.; Park, I.; Chang, T. Macromol. Rapid Commun. 2001, 22, 587-592. It is also interesting to note that thermogelling PLGA-PEG-PLGA (BAB) polymers gelled at lower concentrations than PEG-PLGA-PEG (ABA) polymers, although overall block lengths of the polymers were similar. The effects of monomer ratio and PEG molecular weight on thermal gelation of block copolymers were also systematically investigated. Shim et al., supra. Polymers that are applicable to drug delivery could be synthesized from low-molecular weight PEG (MW less than 2000). Even though PLGA-PEG-PLGA tri-block copolymers have shown excellent biocompatibility, Youxin, L.; Kissel, T. J. Controlled Release 1993, 27, (3), 247-257; Zange, R.; Li, Y.; Kissel, T. J. Controlled Release 1998, 56, 249-258, biodegradation and biocompatibility of the gel depot formed from thermogelling polymers with the same structure have been assessed after in vivo injection of a polymeric solution. Depending on the polymer structure and the block lengths of polymers, polymeric depots from thermoreversible polymers that were synthesized from PEG, lactide, and glycolide could last for up to 1 month without any noticeable indications of toxicity. Zentner et al., supra.
In addition to linear block copolymers, graft copolymers (PEG-g-PLGA) have been synthesized from PEG-diglycidyl ether, lactide, and glycolide. Jeong, B.; Wang, L.-Q.; Gutowska, A. Chem. Commun. 2001, 16, 1516-1517; Jeong, B.; Kibbey, M. R.; Birnbaum, J. C.; Won, Y.-Y.; Gutowska, A. Macromolecules 2000, 33, 8317-8322; Chung, Y.-M.; Simmons, K. L.; Gutowska, A.; Jeong, B. Biomacromolecules 2002, 3, 511-516. The PEG-g-PLGA polymers have also been reported to possess reverse thermogelling properties. Biodegradable blocks could also be prepared from monomers other than lactide and glycolide for thermogelling polymers. Caprolactone, which can be polymerized by ring-opening polymerization, has been successfully used for the preparation of thermogelling polymers of ABA and BAB structures. Hwang, M. J.; Suh, J. M.; Bae, Y. H.; Kim, S. W.; Jeong, B. Biomacromolecules 2005, 6, 885-890; Bae, S. J.; Suh, J. M.; Sohn, Y. S.; Bae, Y. H.; Kim, S. W.; Jeong, B. Macromolecules 2005, 38, 5260-5265. Caprolactone-based thermogelling polymers have been claimed to be advantageous for handling and reconstitution of polymers for practical applications as drug delivery systems. Biodegradable polyphosphazene or poly(propylene fumarate) blocks have also been utilized for the synthesis of thermogelling systems. Lee, B. H.; Lee, Y. M.; Sohn, Y. S.; Song, S.-C. Macromolecules 2002, 35, 3876-3879; Behravesh, E.; K. Shung, A.; Jo, S.; Mikos, A. G. Biomacromolecules 2002, 3, 153-158.
Thermogelling polymers synthesized from PEG and PLGA have been studied for their applications as drug delivery platforms. GLP-1 (glucagon-like peptide-1) and insulin have been formulated and delivered with thermogelling PLGA-PEG-PLGA polymers. Kwon, Y. M.; Kim, S. W. Pharm. Res. 2004, 21, (2), 339-343; Choi, S.; Baudys, M.; Kim, S. W. Pharm. Res. 2004, 21, (5), 821-31. In vivo studies using rats have shown that thermally formed polymeric depots from the PLGA-PEG-PLGA block copolymer extended the release of the proteins up to 10 days. In addition to proteins, small drug molecules, such as paclitaxel, have been successfully delivered by means of minimally invasive subcutaneous injection. Zentner et al., supra; Jeong, B.; Bae, Y. H.; Kim, S. W. J. Controlled Release 2000, 63, 155-163; Duvvuri, S.; Janoria, K. G.; Mitra, A. K. J. Controlled Release 2005, 108, (2-3), 282-293. Thermogelling polymers composed of PEG and PLGA blocks have also been used for delivery of cells and genes as well as proteins. Zentner et al., supra; Li et al., supra.
Based on previous work, thermogelling polymers hold great promise for their biomedical applications. However, new thermogelling polymers, methods of making, and methods of use are needed to broaden the scope of drugs, proteins, cells, and genes that may be delivered.
In view of the foregoing, it will be appreciated that providing aliphatically modified biodegradable thermogelling polymers, methods of making, and methods of use would be significant advancements in the art.